Alzheimer's disease (AD) is the most common cause of irreversible, chronic dementia. Although AD may be familial in only one-third of all cases, the main justification for studying autosomal dominant cases lies in the accuracy of diagnosis which may be inferred through postmortem examination of other affected family members. More than 270 members of 23 pedigrees with an autosomal dominant form of AD have had skin fibroblast and peripheral blood lymphoblast cultures established. These cultures serve as a renewable source of DNA and cell lines for genetic linkage, viability, and biochemical studies. Recombinant DNA technology has been applied to perform genetic linkage studies in these families with inherited AD. Approximately 75% of the amyloid precursor protein (APP) gene has been sequenced in the Canadian and Italian pedigrees. The beta-amyloid peptide coding exons have been sequenced in 20 pedigrees. No mutations have been detected thus far. It appears that the Familial Alzheimer's disease locus and APP gene on chromosome 21 reside at different locations in these pedigrees. Calcium transients induced in fibroblasts by serum and bradykinin are greater in control than in AD cells. Factors other than abnormal calcium metabolism or signal transduction may explain these observations. Longitudinal investigation of neurotransmitters/neuropeptides in CSF confirm our previous observations. The CSF level of corticotropin releasing factor (CRF) is normal in affected patients. Abnormally low plasma ACTH responses to arecoline suggest central cholinergic involvement in patients with familial AD. Only 25% of at-risk family members tested manifested a normal response to arecoline. Three at-risk subjects who later developed dementia had reductions in CSF MHPG, somatostatin, and regional cerebral glucose metabolism that preceded expression of the disease. Neurochemical and metabolic changes may have potential as biologic markers of AD.